Internal Company Decision

Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD

This is an open-label, two-stage, Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD who progressed with elevated and rising serum C reactive protein (CRP) levels after prior treatment with siltuximab 11 mg/kg every 3 weeks (q3w) without unacceptable toxicity, and is primarily designed to leverage opportunities for intrapatient dose escalation with available clinical, nonclinical, and PK justification as a means to restore or enable disease control.

Enrolling in Stage 1a and Stage 1b of this study in parallel will be up to 6 patients each with siltuximab-relapsed or refractory IL-6-driven iMCD and TAFRO-iMCD patients, respectively, who will undergo intrapatient dose escalation of siltuximab beginning with 22 mg/kg q3w, then possibly dose escalating to 33 mg/kg q3w then 44 mg/kg q3w if clinically indicated in the absence of DLT. The justifications for escalating siltuximab doses up to 44 mg/kg q3w will be based on intrapatient dose escalation and DLT assessments as described below.

Inclusion Criteria:

• Documented history of consensus histologic, laboratory, and clinical diagnostic criteria of iMCD.

• Archival and/or baseline incisional/excisional biopsy for retrospective central histologic confirmation of iMCD.

• CDCNRC-defined disease progression on or after prior treatment with siltuximab at 11 mg/kg q3w without unacceptable toxicity within 12 weeks between the last dose of siltuximab and the date of signed patient informed consent form (ICF).

• At least 1 measurable abnormal lymph node mass that is ≥1 cm in its longest transverse diameter as assessed by computerized tomography (CT) scan that has not been previously irradiated.

• Elevated (>10 mg/L) and rising serum CRP in the absence of additional iMCD treatment.

• Evidence of at least an additional one of the following laboratory or clinical signs of iMCD per international, evidence-based consensus diagnostic criteria for HIV or HHV 8-negative iMCD:

  • Anemia, thrombocytopenia, hypoalbuminemia, renal dysfunction, or polyclonal hypergammaglobulinemia.
  • Constitutional symptoms (night sweats, fever (>38°C), weight loss, or fatigue (CTCAE lymphoma B-symptoms score ≥2), large spleen and/or liver, fluid accumulation, eruptive cherry hemangiomatosis/violaceous papules, or lymphocytic interstitial pneumonitis.

• Adequate clinical laboratory measurements within 3 weeks prior to study entry in all parameters below:

  • Absolute neutrophil count ≥1.0 × 109/L, hemoglobin <17 g/dL, and platelets ≥50 × 109/L without transfusion, hematopoietic growth factors, or both for >7 days prior to measurement.
  • AST, ALT, total bilirubin, and alkaline phosphatase ≤5 × ULN.
  • Fasting cholesterol <300 mg/dL and fasting triglyceride <400 mg/dL.

• Age ≥12 years.

Exclusion Criteria:

• Documentation of HIV or HHV-8 infection or presence of other infection-related disorders that resemble clinical or histological features of iMCD

• Diagnosis of any malignant/benign lymphoproliferative disorders

• Diagnosis of autoimmune/autoinflammatory disease

• Treatment with corticosteroids (prednisone dose-equivalent >1 mg/kg/day) within 7 days prior to study entry.

• History of solid organ transplant, allogeneic bone marrow transplant, or allogeneic peripheral blood stem cell transplant.

• Previous malignancy with the following exceptions:

  • Past malignancy with treatment that was completed at least 2 years before signing informed consent and the patient has no evidence of disease, or
  • Concurrent malignancy that is clinically stable and does not require tumor-directed treatment (eg, nonmelanoma skin cancer and carcinoma in situ)

No masking